The small
intestine of the human consists of three portions: duodenum (10
inches), jejunum (8 feet), and ileum (12 feet). The wall of the
intestine is made up of mucosa and submucosa.

The mucosa, in turn, is divided
into three layers: epithelium, laminapropria and
muscularismucosae.
Evaginations of the mucosa, termed villi, project into the intestinal
lumen. Between the villi are crypts; these are minute depressions
of the mucosa that extend into the lamina propria. There are 3 crypts for
each villus.

The intestinal epithelium
is a continuous single layer of cells that covers the entire surface of
the intestinal wall facing the intestinal lumen. It covers the villi, the
area between the villi as well as the sides and bases of the crypts.

The intestinal epithelium
consists of 4 cell types: the columnarabsorptivecell
(making up 90% of the total cells), the gobletcell (9.5%
of total), the Panethcell and the undifferentiated columnar
cell.

Covering the sides and tips
of the villus is the columnar absorptive cell. This cell has, on its luminal
surface, projections termed microvilli. These microvilli in turn,
have projections of glycoprotein molecules which are termed the glycocalyx.
This glycocalyx has enzymatic properties, i.e. it is a saccharidase, alkaline
phosphatase and aminopeptidase. These glycoprotein enzymes have a hydrophobic
end imbedded in the lipid of the cell membrane and a hydrophilic end projecting
into the lumen. This hydrophilic end contains the substrate binding site.
The function of the columnar absorptive cell is the absorption of water,
minerals, amino acids and simple sugars.

The goblet cells are interspersed
among the absorptive columnar cells of the epithelium along the sides and
tips of the villi. The apical two-thirds of these cells are filled to the
point of distention by an accumulation of membrane-bound mucin secretory
granules. Once secreted from these unicellular glands the mucous forms
a luminal lining lying on top of the glycocalyx of the microvilli. The
mucous lubricates and forms a barrier which protects the mucosal epithelium
from potentially noxious intraluminal substances. Goblet cell secretion
of mucin is induced by enterotoxins of Escherichia coli and Vibrio
cholerae as well as by immune complexes.

The Paneth cells occur in
small groups at the base of the intestinal crypt. These have both phagocytic
and secretory properties and thus provide the first line of immune defense
against intestinal microorganisms. They secrete lysozyme (which dissolves
the cell wall of bacteria) and secretory IgA.

The undifferentiated columnar
cells occur at the base of the crypt where they are interspersed with the
Paneth cells. This is the cell production site of the epithelium. These
cells are in constant replication; they are the progenitor of the columnar
absorptive cell, the goblet cell and Paneth cell.

Underlying the intestinal
epithelium is the lamina propria. This is a compact stroma, composed mainly
of reticular and elastin fibers. It has extensive beds of blood and lymph
capillaries and it is into these that the absorbed food matter passes.
Plasma cells and lymphocytic cells are especially numerous in this tissue,
the latter often being amassed into solitary or aggregated lymph follicles
(Peyer'spatches). There is extensive trafficking of lymphocytes
through the Peyer's patches. Thus, this presents a second line of immune
defense against microbial invasion from the lumen of the intestine.

The muscularis mucosa is
a thin bilaminar plexus of circular (inner) and longitudinal (outer) smooth
muscle fibers which clearly demarcates the mucosa and submucosa. The muscularis
mucosa enables alteration of the focal conformation of the mucosa independent
of other movements of the digestive tract, increasing its contact with
food.

PHYSIOLOGY:

Most cells formed from the
undifferentiated columnar cell at the base of the crypt, migrate along
the sides of the villi up to the tip of the villi where they are sloughed
off. As they migrate they differentiate into the absorptive columnar cell
or the goblet cell. This is a continuous process whereby the cells of the
epithelium are replaced every 3 days. The rapidly replicating undifferentiated
columnar cells are almost continually undergoing mitosis which makes them
especially sensitive to the effects of radiation therapy, cancer chemotherapy
and various toxins and enzymes of microbial cells. When their reproduction
is interrupted, the other cells of the epithelium continue to migrate and
slough off. This disrupts the epithelium which causes 3 major effects:
compromization of the first line of microbial defense, malabsorption and
diarrhea.

The intestine absorbs both
exogenous fluids and its own secretions. The secretions of the intestine
and digestive glands are so great that, were they not resorbed, death from
dehydration would result in 24 hours.

Daily flux of gut water and
sodium.

Gut Water

ml/day

Na, mM/day

Oral intake

2,000

50-100

Saliva

1,000

50

Gastric juice

2,000

100

Pancreatic juice

2,000

200

Bile

1,000

150

Intestine secretion

6,200

840

Sum

14,200

1,440

Transit ileum to colon

1,500

200

Fecal

100-160

5

One or more central arterioles
carry arterial blood to the tip of a villus, and near the tip the arterioles
break into a rich capillary network that descends the villus just beneath
the bases of the epithelial cells. Thus, blood shoots up the villus as
in a fountain and then falls back around the central stream. This arrangement
permits countercurrent exchange of absorbed substances between the descending
network and the ascending vessels.

Only a few of the absorptive
processes are regulated. The intestine indiscriminately absorbs water,
the major electrolytes, and the products of digestion of foodstuffs, but
absorption of calcium and iron is adjusted to the body's needs. Three properties
of the intestinal mucosa determine its handling of water and electrolytes:

1. Gradient of permeability.
Permeability of the intestinal mucosa to water and electrolytes is high
in the duodenum and jejunum. It decreases
along the length of the intestine until permeability in the ileum is low.
The tight junctions between intestinal epithelial cells
are the site of most permeation by water and electrolytes. In the duodenum
and jejunum they are "leaky" tight junctions. Water
and electrolytes can pass through them in either direction, depending upon
the effective osmotic gradient for water or the electrochemical
gradient for an electrolyte. The tight junctions are cation-selective;
that is, cations such as Na+ and K+ pass through
the junctions more rapidly than do anions such as Cl- and HCO3-.
The junctions are not, however, absolutely cation-selective.
Divalent ions such as Mg++, Ca++ and SO4--
penetrate the junctions only slightly, if at all, and uncharged molecules
above 200 mW are excluded.

2. Na+ - H+
exchange. Throughout the length of the small intestine there is exchange
of Na+ from the lumen for H+ from the cell interior
across the apical membrane of the intestinal epithelial cells. Na+
is pumped out of a cell across its basolateral border, and the
concentration of Na+ within the cell is relatively low. In addition,
the potential difference across the apical membrane is positive
outward and negative inward. Consequently, there is an electrochemical
gradient drawing Na+ from the luminal fluid into the cell.
Exit of Na+ from cell to interstitial fluid is accomplished
by an energy-consuming pump in the basolateral membrane. Although
a number of H+ ions are extruded equivalent to the number of
Na+ ions entering the cells, the gradient of H+ concentration
across the apical membrane of the cell is very small; extrusion requires
very little energy, and that energy may be derived
from the Na+ gradient. As Na+ is absorbed, Cl-
follows passively.

3. Cl- - HCO3-
exchange. In the ileum, but not in the jejunum, there is equal exchange
of Cl- from the luminal fluid for HCO3-,
from the cell
interior across the apical membrane of the epithelial cells. Cl-
entering the cell is extruded across the basolateral border into
interstitial fluid.

The Large Intestine

ANATOMY:

The submucosa
and the muscularis mucosa of the large intestine do not vary significantly
from that of the small intestine except for the
profusion of lymphocytes, macrophages and plasma cells that locally produce
IgA within the lamina propria. This is a reflection
of the more than 500 species of bacteria present in the lumen of the large
intestine.

The mucous
membrane of the large intestine does differ from that of the small intestine
in several aspects:

1. There
are no villi. 2. The
intestinal crypts are larger, more numerous and more densely packed. 3. One-fourth
of the epithelial cells are goblet cells (vs. one-tenth in the small intestine).
Thus the large intestine is well lubricated
with a heavy mucous. 4. There
are no Paneth cells.

PHYSIOLOGY:

All that is left of the chyme,
which formed the contents of the upper small intestine, by the time it
reaches the ileum is the unabsorbable constituents of the diet such as
dietary fiber, lignum, waxes, high melting point fats, insoluble or unabsorbable
salts and the bodies of the saprophytic bacteria, which inhabit the lower
small bowel, plus about 2 liters of water per day containing Na+
in concentrations isotonic with plasma. In contrast to the small intestine,
the large intestine absorbs all of the fluid and Na+ that enters
it, except for the 100 ml fluid lost per day in the feces and about 4 mmol
of Na+. If in excess of 3 liters of water enters the cecum,
the upper limit of the colon's absorptive capacity is exceeded and diarrhea
results.

Water moves passively with
Na+ and Cl-, but neither the movement of these ions
nor of water is unidirectional or isotonic. Na+ and its accompanying
anion and water diffuse fairly easily back into the lumen, but the net
flow is usually in the direction of active absorptions into the portal
blood. This is usually 4 times as rapid as back diffusion into the lumen.

Consider the gastrointestinal
tract as a tube through the center of the body extending from the oral
cavity to the anus. The walls of this tube serve as the interface between
the external environment and the body. Through this tube passes all of
the liquid and solid material we ingest. Carried with the ingested material
are bacteria which tend to colonize those parts of the tube that offer
a suitable environment for growth, establishing a "normal" flora for each
part of the tube.

Thus, we see that each end
of the tube, the oral cavity and the colon, are heavily colonized while
the central part of the tube, the esophagus, stomach, duodenum, jejunum
and the proximal half of the ileum, are lightly colonized.

Each portion of the gastrointestinal
tract has special anatomic, physiological and biochemical barriers to infection
by the normal flora or pathogenic microorganisms. When there barriers are
breached by microorganisms or their toxins we have disease. The barriers
to infection of the GI tract include:

A. An
unbroken mucosal epithelium covering all parts of this system. Under normal
conditions epithelial cells are continually
sloughed off and replaced. As the cells are sloughed off, any microorganisms
attached to these cells or within these cells
enter the internal chyme and are excreted from the body. If the sloughing
process is interfered with, microorganisms more
easily form foci of infection. If the normal replacement process is interfered
with, as in radiation therapy or cancer
chemotherapy, there is ulceration of the mucosa with the resulting clinical
symptoms of nausea and vomiting. Infection of the
ulcer will lead to septicemia and fever.

B. The
glycocalyx, a glycoprotein and polysaccharide layer that covers the surface
of the epithelial cells. This presents a thick,
relative to the size of bacteria, physical barrier as well as a chemical
trap that binds microorganisms.

C. Mucous.
The mucous plays two roles in disease prevention; it acts as a physical
barrier in preventing bacterial access to the
epithelial cells and it coats the bacteria, making it easier to remove
them via peristalsis.

D. Acidity
of the stomach. The normal pH of the stomach is less than 4. This acidity
spills into the small intestine establishing a
pH gradient that prevents most bacteria from colonizing the stomach, duodenum,
jejunum and upper half of the ileum.
Because of this, the majority of ingested pathogens never reach the intestinal
tract. Over 99.9% of ingested bacteria are killed
after 30 minutes exposure to stomach acidity. Alteration of the acid barrier
of the stomach by disease, surgery, drugs or
antacids increases the survival of pathogens across this organ and may
lead to microbial infection downstream. For example,
the inoculum of Vibrio cholerae required to cause disease is 108
organisms. If gastric acidity is neutralized by 2 gm of sodium
bicarbonate, only 104 ingested organisms are required to cause
disease.

E. Bile.
Bile solubilizes lipids; it thus inactivates those organism having a lipid
envelope. All enveloped viruses and many bacteria
are thus prevented from growing in areas of high bile salts. Obstruction
of the flow of bile due, for example, to gallstones has
two effects: downstream from the blockage and into the intestine non-normal
flora (i.e., organisms with an outer lipid
membrane) can proliferate and cause disease and upstream from the block
bile salts accumulate and initiate a cycle of
inflammation and damage to the gallbladder wall which often becomes a site
of infection (cholecystitis)

G. In
children lactoferrin in the mother's milk has a similar function to IgA.

H. While
blood cells, especially neutrophils, have their final stopping point in
the intestine. They play an undetermined role in
controlling pathogens and maintaining the balance of normal flora.

I. Gut
motility. Peristalsis contributes to the health of the gut by:

1. Aiding in the fluid absorption process
2. Maintaining appropriate dilution of indigenous enteric microflora
3. Ridding the host of pathogenic microorganism by hindering adherence
of micro-organisms to receptors in the epithelial wall.

J. Peyer's
patches. These are whitish unencapsulated patches of lymph follicles in
the mucosa and sub-mucosa of the small
intestine which provide a "gut-homing" site for lymphocytes. This allows
certain antigen-specific lymphocytes to come into
contact with their appropriate antigen in the microenvironment of the Peyer's
patches. In addition there is non-specific
lymphocyte trafficking through the Peyer's patches; about 1-2% of the lymphocyte
pool recirculate each hour providing a ready
source of white blood cells. The intestinal mucosa demonstrates a state
of "physiologic inflammation" in the lamina propria,
with neutrophils, macrophages, plasma cells and lymphocytes present - suggesting
a constant battle to maintain the integrity
of the mucosa.

K. Normal
flora. Of the normal microflora, 99.9% are anaerobes, mainly members of
the genera
Bacteroides,
Clostridium, and
Peptostreptococcus. The remaining organisms are aerobes or facultative
cells of the genera Escherichia, Proteus and
Pseudomonas as well as other less numerous species. These normal non-pathogenic
flora compete with potential pathogens
for nutrients and intestinal receptor sites, thus keeping them from causing
disease.

The gastrointestinal tract
is subjected to continual challenge by pathogenic microorganisms but is
well protected by the various barriers discussed above. It is only when
one or more of these barriers is breached that we have disease. Some of
the more common factors that compromise the human are:

A. Ingestion
of antacids which neutralize stomach and upper intestinal acidity and allow
microorganisms to proliferate on areas
that are normally lightly colonized.

H. Anatomic
alterations. Obstructions to the flow of liquids remove one of the most
powerful defensive mechanisms of the
gastrointestinal tract. Thus, stones in the gallbladder that impede the
flow of bile predispose the biliary tree to infections. The
presence of large diverticuli or the surgical formation of intestinal "blind
loops" create sites with reduced flow of intestinal
contents, leading to bacterial overgrowth and metabolic derangements.